ES2671036T3 - A process of converting a solid (meth) acrylate copolymer into a dispersed form by means of a dispersing agent - Google Patents

Abstract

A process of converting a solid (meth) acrylate copolymer into a dispersed form by preparing an aqueous dispersion comprising components (a) a (meth) acrylate copolymer that is composed of free radical polymerized methyl methacrylate, ethyl acrylate and a 2-trimethylammonioethyl methacrylate salt, present in solid form as a powder or as a granule, where the (meth) acrylate copolymer is composed of 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and 7 to 2% by weight of a 2-trimethylammonioethyl methacrylate salt, in which the percentages by weight add up to 100% or the (meth) acrylate copolymer is composed of 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and more than 7 to 12% by weight of a 2-trimethylammonioethyl methacrylate salt, in which the weight percentages add up to 100%, (b) up to 50% by weight calculated based on copolym ero (meth) acrylate (a) of a dispersing agent selected from groups of (b) i) plasticizers in combination with emulsifiers and / or (b) ii) selected from one or more of the groups consisting of (b) ii - i) fatty alcohols having 6 to 18 carbon atoms, (b) ii - ii) water soluble salts of saturated or unsaturated carboxylic acids having 6 to 18 carbon atoms, (b) ii - iii) monocarboxylic acids unsubstituted having 6 to 18 carbon atoms, (b) ii-iv) hydroxycarboxylic acids having 6 to 18 carbon atoms. (c) water mixing components (a), (b) and (c) to give a suspension that converts to an aqueous dispersion during the conversion of the solid (meth) acrylate copolymer into the dispersed form, where the plasticizer with respect Component (b) is selected from the group consisting of alkyl citrates, alkyl phthalates, alkyl sebacate, polyethylene glycols or mixtures thereof and the emulsifier with respect to component (b) is selected from the group consisting of alkyl sulfates fatty, sucrose stearate, polysorbates or mixtures thereof or sodium salts of fatty alcohol sulfates, sulfosuccinates, partial esters of fatty acids of polyvalent alcohols, partial esters of fatty acids of sorbitan, partial esters of fatty acids of polyhydroxyethylene sorbitan ( monoester), fatty alcohol ethers and polyhydroxyethylene, fatty acid esters and polyhydroxyethylene or block copolymers of ethylene oxide and propylene oxide, characterized in that the (meth) acrylate copolymer is converted into the dispersed form through the presence of the dispersing agent at a temperature below 45 ° C.

Description

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DESCRIPTION

A process of converting a solid (meth) acrylate copolymer into a dispersed form by means of a dispersing agent

The present invention relates to a process of converting a solid (meth) acrylate copolymer into a dispersed form by means of a dispersing agent. The aqueous dispersion contains a cationic (meth) acrylate copolymer and a dispersing agent to facilitate the dispersion step. The dispersion step can be carried out at a lower temperature.

Technical background

US 4737357 describes a method of producing an aqueous film-forming dispersion and coating agent for pharmaceutical products comprising a copolymer of (meth) acrylate which is composed of free radical polymerized methyl methacrylate, ethyl acrylate and chloride. 2- trimethylammonioethyl methacrylate, in which the dispersion step is carried out at temperatures of 60 to 80 ° C.

EP-A 0 463 877 describes pharmaceutical compositions with delayed active ingredient release consisting of a core with a pharmaceutical active ingredient such as a monolayer coating film comprising a water repellent salt and an insoluble ethyl acrylate copolymer in water, methyl methacrylate and trimethylammonioethyl methacrylate chloride. The water repellent salt may be, for example, Ca stearate or Mg stearate. Sigmoid release representations are obtained.

EP-A 0 436 370 describes pharmaceutical compositions with delayed active ingredient release consisting of a core with a pharmaceutical active ingredient and an organic acid and an external coating film that has been applied by aqueous spraying and is an acrylate copolymer of ethyl, methyl methacrylate and trimethylammonioethyl methacrylate chloride. In this case, representations of sigmoid release are also obtained.

WO 00/19984 describes a pharmaceutical preparation consisting of (a) a core comprising an active ingredient, when appropriate a conventional pharmaceutical vehicle and additives, and the salt of an organic acid whose proportion in the weight of the core amounts to 2 , 5 to 97.5% by weight, and (b) an external coating film consisting of one or more copolymers of (meth) acrylate and, where appropriate, conventional pharmaceutical excipients, where 40 to 100% by weight of (meth) acrylate copolymers consist of 93 to 98% by weight of Ci to C4 alkyl esters polymerized by free radicals of acrylic or methacrylic acid and 7 to 2% by weight of (meth) acrylate monomers with an amino group quaternary in the alkyl radical and may, where appropriate, be present in a mixture, with 1 to 60% by weight of one or more additional (meth) acrylate copolymers that are different from the first (meth) acrylate co-polymers mentioned swim and are composed of 85 to 100% by weight of Ci to C4 alkyl esters polymerized by free radicals of acrylic or methacrylic acid and, where appropriate, up to 15% by weight of additional (meth) acrylate monomers with basic groups or acid group in the alkyl radical. Particularly, a 65 percent by weight methyl methacrylate, 30 percent by weight ethyl acrylate and 5 percent by weight trimethylammonioethyl methacrylate chloride (EUDRAGIT® RS) or a 60 percent copolymer is used by weight of methyl methacrylate, 30 percent by weight of ethyl acrylate and 10 percent by weight of trimethylammonioethyl methacrylate chloride (EUDRAGlT® RL).

The automatic translation of the unexamined publication KR1996-000227 (Reg. No. KR0128855; application No. KR1994-014987) describes a process for preparing sustained release pellet formulation. Diltiazem pellets are coated with an aqueous dispersion prepared from a ready-to-use commercially available EUDRAGIT® RS 30D dispersion in which stearic acid, gum arabic and sodium lauryl sulfate are dissolved to give the final coating composition.

US 2008/0152595 A1 describes methods and compositions for deterring oral abuse of administered pharmaceutical products. Dry compositions comprising pharmaceutical active ingredients such as oxycodone, EUDRAGIT® RS in powder form, plasticizers and emulsifiers are used to produce direct compression controlled release capsules. Direct compression compositions are intended for oral ingestion.

WO 03/057199A1 describes adhesive and binders for dermal or transdermal treatment systems.

WO 02 / 09675A1 describes an eletriptan particulate composition showing a sigmoid controlled release pattern.

EP 0352800A2 describes an aqueous polymer dispersion of cellulosic and acrylic based polymers for preparing pharmaceutical dosage forms and dosage forms thereof.

WO 01/68058 describes a multilayer pharmaceutical product for colon release.

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Problem and solution

Regarding the dispersions comprising a copolymer of (meth) acrylate which is composed of methyl methacrylate, ethyl acrylate and 2-trimethylammonioethyl methacrylate, no method was provided in the technical background that allowed the preparation of aqueous dispersions as a coating agent or binding agent for oral or dermal pharmaceutical preparations at lower temperatures. Instead, in the state of the art, the preparation of aqueous dispersions as a coating agent or binding agent for oral or dermal pharmaceutical preparations, whose dispersion is containing said copolymers of cationic (meth) acrylate, the preparation of said dispersion includes a heating stage at high temperatures of approximately 60 to 85 ° C which is expensive and involves respective complicated devices.

In addition, there is a desire to facilitate the preparation of said aqueous dispersions.

Therefore, the object of the present invention was to provide a method of preparing a dispersion as a coating agent or binding agent for oral or dermal pharmaceutical preparations, whose dispersion contained a cationic (meth) acrylate copolymer in which the step of dispersion could be carried out at a lower temperature, specifically the object was to provide a method that would allow faster and easier preparation of said dispersions.

The technical problem was solved by a process of converting a solid (meth) acrylate copolymer into a dispersed form by preparing an aqueous dispersion comprising the components

(a) a copolymer of (meth) acrylate which is composed of free radical polymerized methyl methacrylate, ethyl acrylate and a 2-trimethylammonioethyl methacrylate salt, present in solid form as a powder or as a granule, where

the (meth) acrylate copolymer is composed of 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and 7 to 2% by weight of a salt of 2-trimethylammonioethyl methacrylate, preferably chloride of 2-trimethylammonioethyl methacrylate, in which the percentages by weight total 100% or

The (meth) acrylate copolymer is composed of 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and more than 7 to 12% by weight of a salt of 2-trimethylammonioethyl methacrylate , preferably 2-trimethylammonioethyl methacrylate chloride, in which the weight percentages total 100%,

(b) up to 50% by weight calculated based on the (meth) acrylate copolymer (a) of a dispersing agent selected from the groups of

(b) i) plasticizers in combination with emulsifiers and / or

(b) ii) selected from one or more of the groups consisting of

(b) ii-i) fatty alcohols having 6 to 18 carbon atoms,

(b) ii-ii) water soluble salts of saturated or unsaturated carboxylic acids having 6 to 18 carbon atoms,

(b) ii-iii) unsubstituted monocarboxylic acids having 6 to 18 carbon atoms,

(b) ii-iv) hydroxycarboxylic acids having 6 to 18 carbon atoms.

(c) water

mixing components (a), (b) and (c) to give a suspension that becomes an aqueous dispersion during the conversion of the solid (meth) acrylate copolymer into the dispersed form,

wherein the plasticizer with respect to component (b) is selected from the group consisting of alkyl citrates, alkyl phthalates, alkyl sebacate, polyethylene glycols or mixtures thereof and

The emulsifier with respect to component (b) is selected from the group consisting of fatty alkyl sulfates, sucrose stearate, polysorbates or mixtures thereof or of sodium salts of fatty alcohol sulfates, sulphosuccinates, partial fatty acid esters of polyhydric alcohols, partial esters of sorbitan fatty acids, partial esters of polyhydroxyethylene sorbitan (mono-ester) fatty acids, ethers of fatty alcohols and polyhydroxyethylene, esters of fatty acids and polyhydroxyethylene or block copolymers of ethylene oxide and propylene oxide,

characterized by that

The (meth) acrylate copolymer is converted into the dispersed form by means of the presence of the dispersing agent at a temperature below 45 ° C.

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One of the advantages of the present invention is that ready-to-use dispersions are provided that do not involve expensive heating steps for their preparation. The process according to the invention is completely different from the so-called solvent evaporation processes where large amounts of organic solvents are used to dissolve a certain polymer first before transferring them to aqueous dispersions after removing the organic solvent by evaporation.

Dispersion composition

The aqueous dispersion consists of water and dry substance (solids content) that add up to 100%. The dry substance of the aqueous dispersion may consist of at least 10, at least 20, at least at least 30, at least 40, at least 50, at least, at least 60, at least 70, at least 80, at least 90% by weight of components (a) and (b) and up to 90, up to 80, up to 70, up to 60, up to 40, up to 30, up to 20 , up to 10% by weight of pharmaceutical, nutraceutical or cosmeceutical active ingredients or also pharmaceutical, nutraceutical or cosmeceutical excipients that are different from components (a) and (b). The components (a) and (b) and, if present, the pharmaceutical, nutraceutical or cosmeceutical active ingredients or the additional pharmaceutical, nutraceutical or cosmeceutical excipients that are different from the components (a) and (b) total 100% of the solids content of the aqueous dispersion. Most preferably, the dry substance of the aqueous dispersion may consist of 100% of the components (a) and (b).

The solids content of the dispersion may be in the range of 10 to 50, preferably 15 to 40, preferably 15 to 30% by weight based on the total weight of the dispersion. Thus, the water content (c) can be from 90 to 50, preferably from 85 to 60, preferably from 85 to 70% by weight based on the total weight of the dispersion.

Component

Component (a) is a copolymer of (meth) acrylate which is composed of free radical polymerized methyl methacrylate, ethyl acrylate and a 2-trimethylammonioethyl methacrylate salt. These types of copolymers can be used for sustained release coating compositions or sustained release matrix compositions.

Component (a) can be used in the inventive process in solid (dry) form as a powder, for example, with an average particle size of 1 to 500 pm or as a granule with an average particle size greater than 500 to 5000 pm to become the dispersed form.

In addition, component (a) is a copolymer of (meth) acrylate composed of 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and 7 to 2% by weight of a methacrylate salt of 2-trimethylammonioethyl, preferably 2-trimethylammonioethyl methacrylate chloride (type EUDRAGIT® RS), in which the weight percentages total 100%.

A specifically suitable copolymer comprises 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammonioethyl methacrylate chloride (EUDRAGIT® RS).

In addition, component (a) is a copolymer of (meth) acrylate composed of 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and more than 7 to 12% by weight of a 2-trimethylammonioethyl methacrylate salt, preferably 2-trimethylammonioethyl methacrylate chloride (type EUDRAGIT® RL), in which the weight percentages total 100%.

A specifically suitable copolymer comprises 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammonioethyl methacrylate chloride (EUDRAGIT® RL).

Appropriate (meth) acrylate copolymers are disclosed, for example, in EPA 181 515 or DE 1 617 751. They are polymers that are soluble or swellable regardless of pH and are suitable for drug coatings. A possible production process to be mentioned is block polymerization in the presence of an initiator that forms free radicals and dissolves in the monomer mixture. The polymer can also be produced by block polymerization, in solution or by precipitation.

The polymer (a) can thus be obtained in the form of a fine powder, which can be achieved in the case of block polymerization by crushing or grinding and in the case of polymerization in solution and by precipitation, for example, by drying by spray.

Vitreous transition temperatures

The glass transition temperature of said copolymer comprising 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammonioethyl methacrylate chloride (EUDRAGIT® RS) is approximately 65 ° C .

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The glass transition temperature of said copolymer comprising 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammonioethyl methacrylate chloride (EUDRAGIT® RL) is approximately 70 ° C .

The glass transition temperature can be determined as the average value in the glass transition interval according to ISO 111357 at a heating rate of 20 K / min in the second thermal cycle.

By means of the present invention, the dispersion step can be carried out well below the glass transition of the copolymers (a) preferably at a temperature below 50 ° C, more preferred below 45 ° C, further preferred below 35 ° C, even more preferred below 30 ° C and most preferred at a temperature in the range of 15 ° C to 25 ° C.

Process to prepare the copolymer (a)

The preparation of the copolymer by free radical polymerization of the monomers as such is well known in the art (see, for example, EP 0 704 207 and EP 0 704 208). The copolymer can be produced by emulsion polymerization in the aqueous phase in the presence of preferably anionic emulsifiers, for example according to the procedure described in DE-C 2 135 073. Production by block polymerization is preferred.

The copolymer can be produced according to the usual methods of radical polymerization in the presence of initiators that form free radicals and optionally in the presence of regulators in order to obtain a certain molecular weight. The average molecular weight can be from 20,000 to 200,000 (g / mol). Preferably, the copolymer is produced by block polymerization.

Dispersing agent (b)

The dispersing agent (b) can be selected from or

the group (b) i) plasticizers in combination with emulsifiers or from a combination of members selected from group (b) i) and group (b) ii).

Role of the dispersing agent (b)

The presence of the dispersing agent (b) in an amount of up to 50, up to 40, up to 20, preferably 5 to 50% by weight calculated based on the (meth) acrylate copolymer (a), is essential to convert the (meth) acrylate copolymer to disperse in water at temperatures below 45 ° C, additionally preferred below 35 ° C, even more preferred below 30 ° C and most preferably at a temperature in the range of 15 ° C to 25 ° C (room temperature).

Without the presence of the dispersing agent (b), the (meth) acrylate copolymer will continue, at temperatures below 50 ° C, in water in the form of a suspension and will not disperse and thus cannot be sufficiently processed in coating agents and union.

Scattered means that the original solid (meth) acrylate copolymer (a) that is after the first contact with water simply suspended in the water becomes more or less uniformly distributed at least 90, preferably at least 99%, giving spherical polymer particles with average particle sizes in the range of 50-1000 nm, preferably in the range of 100-500 nm. Most preferably, the (meth) acrylate copolymer component (a) becomes more or less completely dispersed at 100% or almost 100%.

Preferably, the dispersion process is supported by stirring. Preferably, the suspension is agitated to support the distribution of components (a) and (b) and optionally additional excipients in the water. Stirring can be performed using a simple stirrer or a disperser that applies high shear forces. Agitation times can be in the range of up to 18 hours (overnight), up to 12, up to 8, up to 4 or up to 2 hours. Normally, an aqueous dispersion comprising the (meth) acrylate (a) copolymer component in a completely dispersed form can already be obtained within 30 minutes to two hours.

Components (a) and (b) can be added to water (c) in any order, as a ready-to-use dry mixed composition or as individual components together or one after the other.

Component (b) i) plasticizers in combination with emulsifiers

The process can be carried out in the presence of plasticizers in combination with emulsifiers. Preferably, the content of the plasticizer may be in the range of 1 to 50, preferably in the range of 5 to 40, in the range of 10 to 30% by weight based on the weight of copolymer of (meth) acrylate (a). The content of the emulsifier may be in the range of 1 to 30, preferably in the range of 5 to 25% by weight based on the weight of (meth) acrylate copolymer (a).

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Component (b) i) can be used alone or in combination with component b ii).

Plasticizers

Plasticizers can influence the functionality of the polymer layer, depending on the type (lipophilic or hydrophilic) and the amount added. The plasticizers achieve a reduction in the glass transition temperature by physical interaction with the polymers and promote film formation, depending on the amount added. Suitable substances may normally have a molecular weight between 100 and 20,000 g / mol and comprise one or more hydrophilic groups in the molecule, for example, hydroxyl, ester or amino groups.

Examples of suitable plasticizers are alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacate, sucrose esters, diethyl sebacate, dibutyl sebacate and polyethylene glycols 200 to 12,000. Preferred plasticizers are triethyl citrate (TEC), acetyltriethyl citrate (ATEC) and dibutyl sebacate (DBS). Mention should also be made of esters that are normally liquid at room temperature, such as citrates, phthalates, sebacates or castor oil. Esters of citric acid and sebacic acid are preferably used.

The plasticizers can be added to the formulation in a known way, directly, in aqueous solution or after thermal pretreatment of the mixture. It is also possible to use mixtures of plasticizers.

Emulsifiers

Preferred emulsifiers with respect to component (b) are nonionic or anionic emulsifiers. Additionally preferred, the emulsifiers with respect to component (b) may be selected from the group consisting of fatty alkyl sulfates, preferably sodium lauryl sulfate, sodium cetyl stearyl sulfate, sucrose stearate, polysorbates, especially polysorbate 80 (Tween® 80) or mixtures of the same.

Anionic emulsifiers

Examples of suitable anionic emulsifiers are

sodium salts of fatty alcohol sulfates, for example sodium lauryl sulfate or sodium cetyl stearylsulfate, sulphosuccinates, for example, sodium dioctylsulfosuccinate,

Nonionic Emulsifiers

Examples of suitable non-ionic emulsifiers are partial esters of fatty acids of polyvalent alcohols, for example, glycerin monostearate,

partial esters of sorbitan fatty acids, for example, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate,

partial fatty acid esters of polyhydroxyethylene sorbitan (mono-ester), for example, polyethylene glycol (20) - sorbitan monolaurate, polyethylene glycol (20) - sorbitan monostearate, polyethylene glycol (20) - sorbitan monooleate,

ethers of fatty alcohols and polyhydroxyethylene, for example, polyhydroxyethylene-cetyl stearyl ether (= Cetomacrogol), polyhydroxyethylene (4) -lauryl ether, polyhydroxyethylene (23) -lauryl ether,

esters of fatty acids and polyhydroxyethylene, for example, polyhydroxyethylene stearate (8), polyhydroxyethylene stearate (40), polyhydroxyethylene stearate (100),

block copolymers of ethylene oxide and propylene oxide, for example, condensates of polyhydroxyethylene and polyhydroxypropylene.

Component (b) ii)

Component (b) ii) can be used alone or in combination with component (b) i).

Pharmaceutically acceptable means that the substances of component (b) ii) used must be toxicologically acceptable and can be used in particular in medicines, nutraceuticals or cosmeceuticals without a risk to patients or clients.

Components b ii) can be divided into additional embodiments of the (sub) components (b) ii - i), (b) ii - ii), (b) ii - iii) and (b) ii - iv).

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Components (b) ii) - i) to iv)

The process according to the invention can be further characterized in that the dispersing agent (b) ii) is selected from one or more of the groups consisting of

(b) ii-i) fatty alcohols having 6 to 18 carbon atoms,

(b) ii-ii) water soluble salts of saturated or unsaturated carboxylic acids having 6 to 18 carbon atoms,

(b) ii-iii) unsubstituted monocarboxylic acids having 6 to 18 carbon atoms,

(b) ii-iv) hydroxycarboxylic acids having 6 to 18 carbon atoms.

Component (b) ii-i) fatty alcohols having 6 to 18 carbon atoms

Components (b) ii-i) are one or more fatty alcohols having 6 to 18 carbon atoms or mixtures thereof.

In a preferred embodiment, the fatty alcohols having 6 to 16 carbon atoms are selected from the group consisting of hexanol, octanol, decanol, dodecanol, tetradecanol or hexadecanol or mixtures thereof, preferably octanol. Preferably, the content of the fatty alcohol is in the range of 1 to 50, 5-40, 8-30% by weight based on the weight of the copolymer (a).

Component (b) ii - ii) water soluble salts of saturated or unsaturated carboxylic acids having 6 to 18 carbon atoms

Component (b) ii-ii) are one or more water soluble salts of saturated or unsaturated carboxylic acids having 6 to 18 carbon atoms or mixtures thereof.

In a particularly preferred embodiment of the present invention, the salt with respect to component (b) ii-ii) is a salt of a saturated monocarboxylic acid (fatty acid), preferably unbranched, preferably unsubstituted, having 6 to 18, preferably 8 to 18 or 10 to 16 carbon atoms.

Preferred water soluble salts of saturated or unsaturated carboxylic acids having 6 to 18 carbon atoms with respect to component (b) may be a salt of a carboxylic acid selected from the group consisting of caprylic acid, caprinic acid, lauric acid, acid myristic, palmitic acid, stearic acid, arachidic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, eleostearic acid and arachidonic acid or mixtures thereof. Alkali metal salts or ammonium salts are preferred. Even more preferred are sodium or potassium salts. Most preferred are salts of caprinic acid or stearic acid or mixtures thereof. Preferably, the salt content of a carboxylic acid is in the range of 0.1 to 20, preferably 1 to 10% by weight percentage based on the weight of the copolymer (a).

Component (b) ii-iii) unsubstituted monocarboxylic acids having 6 to 18 carbon atoms,

Components (b) ii-iii) are one or more unsubstituted monocarboxylic acids having 6 to 18, preferably 6 to 14 carbon atoms, or mixtures thereof. Unsubstituted means unsubstituted in the sense that there are no functional groups present within the molecule, except the carboxyl group.

Preferred unsubstituted monocarboxylic acids having 6 to 14 carbon atoms are saturated. Preferred unsubstituted monocarboxylic acids having 6 to 14 carbon atoms are unbranched.

In another preferred embodiment, the saturated or unsaturated carboxylic acid having 6 to 14 carbon atoms is selected from the group consisting of caproic acid, caprylic acid, caprinic acid, lauric acid, linoleic acid, myristic acid, preferably caprinic acid. Preferably, the carboxylic acid content is in the range of 1 to 50, preferably 5-30% by weight percentage based on the weight of the copolymer (a).

Component (b) ii-iv) hydroxycarboxylic acids having 6 to 18 carbon atoms

Components (b) ii-iv) are one or more hydroxycarboxylic acids having 6 to 18, preferably 6 to 14 carbon atoms or mixtures thereof.

Preferred hydroxycarboxylic acids having 6 to 18 carbon atoms are, for example, citric acid (C6H8O7) and ricinoleic acid (C18H34O3).

Additional examples of hydroxycarboxylic acids having 6 to 18 carbon atoms are dihydroxyethylglycine (bicin), 3-hydroxy-4-trimethylammonium butanoate (carnitine), citric acid, cyclobutyrol, 3-dehydroquinic acid, 2,3-dihydroxy-3 acid -methylpentanoic acid, 2,3-dihydroxybenzoic acid, 2,3-dihydroxymenedic acid, 5-hydroxysalicylic acid (gentisic acid), homocitric acid, isocitric acid, isosacarinic acid, mandelic acid, mevalonic acid, monatin, pamoic acid, prepenic acid, acid salicylic or shikimic acid.

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Preferably, the hydroxycarboxylic acid content is in the range of 1 to 50, preferably 5-30% by weight based on the weight of the copolymer (a).

Use of components (b) ii) in combination with a plasticizer

In a preferred embodiment, the process according to the invention can be carried out using one or more of the components b ii) in combination with a plasticizer. In this case it does not need to be present emulsifier. Preferably, the content of the plasticizer may be in the range of 1 to 50, preferably in the range of 5 to 40, in the range of 10 to 30% by weight based on the weight of the (meth) acrylate copolymer (a).

Water (c)

The aqueous dispersions described herein may contain 50-90%, up to 50%, up to 60%, up to 70%, up to 80% or up to 90% by weight of water, preferably demineralized water. Water and solids normally add up to 100%, so that additional components (b) or excipients that are present and processed in liquid form can be calculated herein as simplified solids. Water must mean at least 95, at least 97, at least 98, at least 99% or 100% pure water. Water may contain, without being crucial for the present invention, up to 5, up to 3, up to 2 or up to 1% of organic solvents such as ethanol, acetone or isopropanol, for example, for the purpose of stabilization against growth. microbial or to reduce the surface tension of the dispersion. However, the most preferred is that no organic solvents are present at all.

Additional processing

According to another aspect of the present invention, a process of producing pharmaceutical forms is provided, in which the above method according to the present invention is followed by manufacturing steps in which the aqueous dispersion is used in pharmaceutically customary processes such as propagation or spraying and obtaining the pharmaceutical form.

Details are found in regular textbooks, for example:

Voigt, R. (1984): Lehrbuch der pharmazeutischen Technologie; Verlag Chemie Weinheim - Deerfield Beach / Florida - Basel.

Sucker, H., Fuchs, P., Speiser, P .: Pharmazeutische Technologie, Georg Thieme Verlag Stuttgart (1991), especially Chapters 15 and 16, pp. 626-642.

Gennaro, A.R. (editor), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton Pennsylvania (1985), Chapter 88, pp. 1567-1573.

List, P.H. (1982): Arzneiformenlehre, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart.

Ready to use composition

The invention also relates to a "ready-to-use" composition comprising a dry mixture of components (a) and (b).

The compositions ready for use according to the invention are different from direct compression compositions, for example, in the form of matrix tablets or capsule subunits that are intended to be used directly for oral ingestion and are not intended to be further processed in the form of an aqueous dispersion. to be used to create coating or bonding compositions. Thus, direct compression compositions for direct oral ingestion as described in, for example, the reference cited in US 2008/0152595 A1 can be expressly excluded from the compositions ready for use according to the present invention.

Typically, the ready-to-use composition may be in the form of a powder, for example, with an average particle size of 1 to 500 pm or a granule with an average particle size greater than 500 to 5000 pm.

A dry mixture should be understood in the sense that at least the component (a) is present in solid form. Component (b) may be present in solid or liquid form. If component (b) is present in liquid form, it will be absorbed by the dry component (a) so that in any case the mixture of components (a) and (b) will produce a dry mixture. The compounds may be combined in a solid form and subsequently dried or may be combined in a molten form, for example by extrusion of the melt.

The "ready-to-use" composition may contain at least 20, at least 30, at least, at least 40, at least 50, at least 60, at least 70, at least 80, at least the 90, at least 95 or 100% by weight of components (a) and (b). The ratio of component (b) to component (a) by weight may be 1: 2 to 1: 20, preferably 1: 2 to 1: 5.

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Optionally, the "ready-to-use" composition may further comprise pharmaceutical, nutraceutical or cosmetic excipients that are different from components (a) and (b), for example, pigments or aromas. Normally, the "ready-to-use" composition may comprise or consist of at least 30, at least 50, at least 70, preferably at least 90% by weight of components (a) and (b) and not more 70, no more than 50, no more than 30, no more than 10% by weight of pharmaceutical, nutraceutical or cosmetic excipients that are different from components (a) and (b).

When the "ready-to-use" composition is mixed with water at a temperature below 50 ° C, preferably below 45 ° C, more preferred below 35 ° C, more preferred below 30 ° C and most preferred at a temperature in the range of 15 ° C to 25 ° C, it first gives a suspension which then becomes an aqueous dispersion comprising at least the (meth) acrylate copolymer in dispersed form.

Preferably, the suspension is agitated to support the distribution of components (a) and (b) and optionally additional excipients in the water. Normally, an aqueous dispersion comprising the (meth) acrylate (a) copolymer component in a completely dispersed form can be obtained within 30 minutes to two hours.

Use

The present invention also provides the use of an aqueous dispersion that originates from the inventive process as described herein or originates from the composition ready for inventive use as described herein as an agent of coating or bonding agent for oral or dermal pharmaceutical, nutraceutical or cosmeceutical preparations. Typical application processes can be wet granulation, spray coating, powder coating, casting, roller coating, knife coating or lamination.

Pharmaceutical, nutraceutical or cosmeceutical excipients

The aqueous dispersions described herein are further characterized in that they can contain up to 90, up to 80, up to 70, up to 60, up to 40, up to 30, up to 20, up to 10% by weight, based on the total solids content, respectively, of the dry weight of the aqueous dispersion, of pharmaceutical, nutraceutical or cosmetic excipients that are different from the components (a), (b). However, the compositions according to the invention may also contain any or essentially any pharmaceutical, nutraceutical or cosmetic excipient. Thus, the compositions may consist essentially or consist of 100% of the components (a) and (b).

The term pharmaceutical, nutraceutical or cosmeceutical excipient is well known to the expert. Such excipients are common in the pharmacy, but also in the field of nutraceuticals or cosmetics, occasionally they are also called habitual additives. Of course, it is always necessary that all the usual excipients or additives used are toxicologically acceptable and can be used in particular in food or in medications without a risk to clients or patients.

Although the requirements are usually higher in the pharmaceutical field, there is a wide overlap of excipients used for pharmaceutical purposes and those used for nutraceutical purposes. Normally, all pharmaceutical excipients can be used for nutraceutical purposes and at least a large number of nutraceutical excipients are allowed to be used for pharmaceutical purposes as well. The excipients may be added to the formulation of the invention, preferably during the mixing of the powder production of the granules, for the coating or bonding of active ingredients, coating of solids or patches or dispersion of semi-solids.

Pharmaceutical, nutraceutical or cosmetic excipients that are different from components (a), (b) and (c) may be contained for practical reasons, for example, to avoid stickiness or to add a color. However, these excipients normally do not contribute or show any effect or almost no effect on the invention itself as claimed herein.

Pharmaceutical, nutraceutical or cosmetic excipients that are different from components (a) and (b) do not contribute to the invention in a narrow sense that is based on the interaction of components (a) and (b). Pharmaceutical, nutraceutical or cosmetic excipients that are different from components (a), and (b) and that may have an essential adverse effect on the main beneficial effects of the present invention, for example the time of preparation or on the viscosity of the dispersion.

Typical pharmaceutical, nutraceutical or cosmetic excipients that are different from components (a) and (b) are known to those skilled in the art. Examples are antioxidants, brighteners, flavorings, flow aids, for example silicates such as pyrogenic or precipitated silica, fragrances, glidants (release agents), penetration promoting agents, pigments, polymers, pore forming agents or stabilizers. They can be used as a processing aid and are intended to ensure a reliable and reproducible preparation process, in addition to good stability during long-term storage, or achieve additional advantageous properties in the pharmaceutical form. They are added to polymer formulations before

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processing and can influence the permeability of the coatings. This property can be used if necessary as an additional control parameter.

Of course, it is always necessary that all pharmaceutical, nutraceutical or cosmetic excipients used are toxicologically acceptable and usable in particular in medicaments, nutraceuticals or cosmeceuticals without a risk to patients or clients.

The amounts used and the use of pharmaceutical, nutraceutical or cosmetic excipients are known to the expert. They are added to the polymer preparations before processing and can influence the permeability of the coatings or matrices, being possible to use them when appropriate as an additional control parameter.

Release Agents:

The release agents normally have lipophilic properties and are usually added to the spray suspensions. They prevent the agglomeration of the cores during film coating. Preferably talc, Mg stearate or Ca stearate, ground silica or kaolin are used. The usual amounts of release agent employed are between 0.5 and 100% by weight based on the dry weight of the (meth) acrylate copolymer (a).

Pigments:

Pigments compatible with the coating agent are in particular those pigments which, if added directly to the (meth) acrylate copolymer dispersion, for example by stirring, in the usual amounts used of, for example, 20 to 200% by weight based in the dry weight of the (meth) acrylate copolymer (a), they do not lead to destabilization of the dispersion, coagulation, signs of a lack of homogeneity or similarly undesirable effects. The pigments to be used are, of course, also non-toxic and suitable for pharmaceutical purposes. With reference to this see, for example, for example: Deutsche Forschungsgemeinschaft, Farbstoffe für Lebensmittel, Harald, Boldt Verlag KG, Boppard (1978); Deutsche Lebensmittelrundschau 74, No. 4, p. 156 (1978); Arzneimittelfarbstoffverordnung AmFarbV of 25.08.1980.

The pigments can be, for example, alumina pigments. Additional examples of pigments are orange-yellow, cochineal red lacquer, colored pigments based on alumina or azo dyes, sulfonic acid dyes, orange-yellow S (E110, CI 15985, FD&C Yellow 6), indigo carmine (E132, CI 73015, FD&C Blue 2), tartrazine (E 102, CI 19140, FD&C Yellow 5), Ponceau 4R (E 125, CI 16255, FD&C Cochineal Red A), quinoline yellow (E 104, CI 47005, FD&C Yellow 10) , erythrosine (E127, CI 45430, FD&C Red 3), azorubin (E 122, CI 14720, FD&C Carmoisine), amaranth (E 123, CI 16185, FD&C Red 2), acid bright green (E 142, CI 44090, FD&C Green S).

The numbers E indicated for the pigments refer to an EU numbering. Referring to this, see also "Deutsche Forschungsgemeinschaft, Farbstoffe für Lebensmittel, Harald Boldt Verlag KG, Boppard (1978); Deutsche Lebensmittelrundschau 74, No. 4, p. 156 (1978); Arzneimittelfarbstoffverordnung AmFarbD.0.0. refer to the authorization in food, drugs and cosmetics by the US Food and Drug Administration (FDA) described in: US Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors: Code of Federal Regulations - Title 21 Color Additive Regulations Part 82, Listing of Certified Provisionally Listed Colors and Specifications (CFR 21 Part 82).

Polymers

As additional excipients, polymers other than the copolymer of (meth) acrylate (a) or of possible polymeric components (b) may be contained in the aqueous dispersion. However, this is indicated only for concentrations that do not essentially affect or disturb the basic functions or the basic character of the aqueous dispersion that is mainly caused and determined by the presence of the (meth) acrylate copolymer (a). Thus, if additional polymers are present, their concentrations are normally lower than those of the (meth) acrylate copolymer (a). Preferably, no more than 90%, no more than 50%, no more than 25%, no more than 10%, no more than 5% by weight of such additional polymers are contained in relation to the (meth) acrylate copolymer ( to). Most preferred, no additional polymers are contained.

Examples of water soluble polymers can be selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose and / or polyvinyl alcohol.

Examples of anionic polymeric materials can be selected from the groups consisting of polymethacrylates, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), cellulose acetate trichlorite or Shellac.

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Production processes of a pharmaceutical form (pellets)

The pharmaceutical form can be produced in a manner known per se by means of usual pharmaceutical processes such as direct compression, compression of dry, wet or sintered granules, extrusion and subsequent rounding, wet or dry granulation or direct pelletization (for example, in plates ) or by joining powders (powder stratification) on beads or free cores of active ingredient (beads) or particles containing active ingredient, by means of spraying or granulating processes in fluidized bed. Application in the form of a coating can take place by means of known and usual processes such as, for example, spray application of polymer solutions or polymer dispersions.

Nutraceuticals

Nutraceuticals can be defined as food extracts claimed to have medical effects on human health. The nutraceutical is normally contained in a medical format such as capsule, tablet or powder in a prescribed dose. Examples of nutraceuticals are resveratrol of grape products as an antioxidant, soluble dietary fiber products, such as psyllium seed husk to reduce hypercholesterolemia, broccoli (sulfane) as a preservative to prevent cancer, and soy or clover (isoflavonoids) for Improve arterial health. Other examples of nutraceuticals are flavonoids, antioxidants, flax seed alpha-linoleic acid, marigold petals beta-carotene or berry anthocyanins. Sometimes, the expression neutraceuticals is used as a synonym for nutraceuticals.

Cosmeceuticals

The term "cosmeceuticals" is used for cosmetic products that are claimed, mainly by those within the cosmetic industry, for having drug-type benefits. Examples of products normally labeled as cosmeceuticals include anti-aging and moisturizing creams. The word is a combination of the words "cosmetic" and "pharmaceutical."

Cosmeceuticals may contain active ingredients such as vitamins, phytochemicals, enzymes, antioxidants and essential oils. However, these components may not necessarily be effective, and if they are effective, cosmeceuticals may not have the active ingredient (s) in an effective formulation or an effective concentration.

An important distinction is based on the method of administration. The "cosmeceutical" label applies only to products applied topically, such as creams, lotions and ointments. Products that are similar in perceived benefits, but ingested orally, are known as nutricosmetics.

Pharmaceutical, nutraceutical or cosmeceutical active ingredients

The aqueous dispersion or ready-to-use composition can be used as a coating and bonding agent in combination with all types of pharmaceutical, nutraceutical or cosmeceutical active ingredients. Pharmaceutically, nutraceutically or cosmetically active principles have in common that they are active ingredients that have a positive effect on the health of an organism, for example, human health. They also have in common that their formulations are often the same or very similar. Frequently the same types of excipients or additives are also used in combination with these types of active ingredients. Pharmaceutically active ingredients are used to cure diseases and to affect the health of an organism positively, for example, human health more or less directly. The nutraceutical active ingredients are used to complement nutrition and thus support the health of an organism, for example, human or animal health indirectly. Cosmetically active principles are indicated to support human health indirectly, for example, by balancing the water content of human skin.

Examples

The present invention will be further explained in more detail by the following examples, which are understood not to limit the scope of the invention in any way.

Comparative example 1: EUDRAGIT® RL dispersion:

50.0 g of EUDRAGIT® RL was dispersed in 237.2 g of demineralized water while stirring with a stirrer at room temperature, then 1.0 g of sodium caprylate and 8.4 g of dibutyl sebacate were added. After 4.5 hours of stirring at 48 ° C a low viscosity dispersion is obtained. The dispersion forms a clear, homogeneous and bright film, indicating functionality, when dried at room temperature.

Comparative example 2: EUDRAGIT® RS dispersion:

30.0 g of EUDRAGIT® RS were dispersed in

138.0 g of demineralized water while stirring on the magnetic stirrer at room temperature, subsequently added

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4.5 g of dibutyl sebacate.

After 24 hours a low viscosity suspension with polymer agglomerates is obtained. The suspension obtained does not form a clear homogeneous film, which indicates lack of functionality, when dried at room temperature.

Comparative example 3: EUDRAGIT® RL dispersion:

30.0 g of EUDRAGIT® RL were dispersed in

138.0 g of demineralized water while stirring on the magnetic stirrer at room temperature, subsequently added

4.5 g of dibutyl sebacate.

After 24 hours a low viscosity suspension with polymer agglomerates is obtained. The suspension obtained does not form a clear homogeneous film, which indicates lack of functionality, when dried at room temperature.

Example 4: EUDRAGIT® RS dispersion (powder):

15.0 g of Polysorbate 80 were dissolved in

580.0 g of demineralized water during stirring and

100.0 g of EUDRAGIT® RS was added during stirring and subsequently 30.0 g of triethyl citrate was added and further stirred at room temperature for an additional 1 hour.

As an agitator an Ultra Turrax, level 1-2 is applied. As a result, an opaque nanopolymer dispersion is obtained. The dispersion is subjected to a sieving step using a 0.2 mm sieve, in which 2-3 percent by weight of the non-dispersed concentrate is retained in the sieve. The dispersion forms a very flexible film when dried at room temperature.

Example 5: EUDRAGIT® RS dispersion (powder):

20.0 g of Polysorbate 80 were dissolved in

680.0 g of demineralized water during stirring and

100.0 g of EUDRAGIT® RS was added during stirring and subsequently 50.0 g of triethyl citrate was added and further stirred at 30 ° C for an additional 1 hour.

As an agitator an Ultra Turrax, level 1-2 is applied. As a result, an opaque nanopolymer dispersion is obtained. The dispersion forms a clear, very flexible adhesive film when dried at room temperature.

Example 6: EUDRAGIT® RL dispersion: In

85.0 g of demineralized water

3.0 g of Tween® 80 and 6.0 g of triethyl citrate were dissolved,

30.0 g of EUDRAGIT® RL 100 (particle size 10 pm) were added slowly

and stirred further at room temperature.

After the polymer was added completely, the viscosity increased sharply. After 1.5 hours the viscosity begins to decrease. After 4 hours an opaque dispersion having low viscosity is obtained. The dispersion forms a clear and flexible film when dried at room temperature.

Example 7: EUDRAGIT® RS dispersion: In

58.0 g of demineralized water

4.5 g of Tween® 80 and 7.5 g of triethyl citrate were dissolved,

30.0 g of EUDRAGIT® RS 100 (10 pm particle size) were added slowly

and stirred further at room temperature.

After the polymer was added completely, the viscosity increased sharply. 1.25 g of ketoprofen was added to the mixture and stirred with a spatula for 10 min, however the viscosity remains high. The

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The mixture is diluted to 35% by dry weight in order to be able to produce a film. After 1.5 hours of stirring with the spatula the viscosity begins to decrease. After 4 hours an opaque dispersion having medium viscosity is obtained. The dispersion forms a sticky, clear and very flexible adhesive film when dried at room temperature

Example 8: EUDRAGIT® RL dispersion: In

154.2 g of demineralized water

7.5 g of Polysorbate 80 and 15.0 g of TEC were mixed and added

50.0 g of EUDRAGIT® RL PO. After stirring for 2.5 hours at room temperature an opaque dispersion having low viscosity is obtained.

The dispersion forms a clear, bright and very flexible film when dried at room temperature.

Example 9: EUDRAGIT® RL dispersion: In

165.4 g of demineralized water

2.31 g of Tween® 80 and 4.62 g of triethyl citrate were mixed for 2 minutes and slowly added

23.07 g of EUDRAGIT® RL (particle size 10 pm) and stirred further at a temperature of 25 to less than 50 ° C.

Once the mixture had reached a temperature of 30 ° C, the viscosity increased strongly. After 15 minutes no polymer particles could be detected under the microscope. After an additional 10 minutes, the mixture was cooled to room temperature, and a dispersion having low viscosity is obtained which forms a clear, flexible and glossy film when dried at room temperature.

Example 10: EUDRAGIT® RS dispersion forming an adhesive film: In

84.5 g of demineralized water

2.14 g of Polysorbate 80 was stirred and

4.29 g of triethyl citrate for 2 min on a magnetic stirrer, then 8.57 g of EUDRAGIT® RS were added, and further stirred. After stirring for

24 hours at room temperature a dispersion having low viscosity is obtained which forms a clear sticky film when dried at room temperature.

This adhesive film cannot be removed from a glass plate coated with Teflon®.

Comparative Example 11: Dispersion of EUDRAGIT® RL:

30.0 g of EUDRAGIT® RL were dispersed in

132.1 g of demineralized water while stirring with a helix stirrer at room temperature, subsequently 18.0 g of Polysorbate 80 33.33% and 9.0 g of triethyl citrate were added.

After 2 hours of stirring at 48 ° C a low viscosity dispersion is obtained. The dispersion forms a clear, very flexible, homogeneous and bright film, which indicates functionality, when dried at room temperature.

Comparative example 12: EUDRAGIT® RL dispersion:

50.0 g of EUDRAGIT® RL powder was dispersed in

230.0 g of demineralized water while stirring with a helix stirrer at room temperature, 15.0 g of 33.33% Polysorbate 80 and 5.0 g of triethyl citrate were subsequently added.

After 2 hours of stirring at 48 ° C a low viscosity dispersion is obtained. The dispersion forms a clear, homogeneous and bright film, indicating functionality, when dried at room temperature.

Comparative Example 13: Dispersion of EUDRAGIT® RL:

50.0 g of EUDRAGIT® RL 100 granules were dispersed in

230.0 g of demineralized water while stirring with a helix stirrer at room temperature, 15.0 g of 33.33% Polysorbate 80 and 5.0 g of triethyl citrate were subsequently added.

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After 3 hours of stirring at 48 ° C a low viscosity dispersion is obtained. The dispersion forms a clear, homogeneous and bright film, indicating functionality, when dried at room temperature.

Comparative example 14: EUDRAGIT® RL dispersion:

10.0 g of Polysorbate 80 were mixed

10.0 g of triethyl citrate for 5 min in

480.0 g of demineralized water while stirring with a propeller shaker at room temperature, 100.0 g of EUDRAGIT® RL were subsequently added.

After 2 hours of stirring at 45 ° C a dispersion is obtained which forms a clear flexible film when dried at room temperature or 40 ° C.

To this dispersion was added a mixture of

12 g of HPMC,

18.0 g of Mg stearate and

120.0 g of demineralized water and stirred for 2 hours. The HPMC-Mg stearate suspension was poured during stirring to the RL dispersion and further stirred for 1 hour. The dispersion-suspension was then lyophilized.

40.0 g of lyophilized product were redispersed in 160 g of desm water. by gentle agitation with propeller stirrer at room temperature. The "ready to use" spray suspension was applied on diprophilin pellets without any problem. An immediate release coating with 20% applied on dry substance was obtained.

Example 15: Dispersion of EUDRAGIT® RL:

30.0 g of EUDRAGIT® RL were dispersed in

144.0 g of demineralized water

3.0 g of PS 80 while stirring on the magnetic stirrer at room temperature, subsequently added

6.0 g of glycerol, after 1 hour of stirring, 6 g of ATBC was added.

After an additional 2 hours of stirring a low viscosity dispersion is obtained. The dispersion-suspension forms a clear, flexible homogeneous and bright film, indicating functionality, when dried at room temperature.

Example 16: Dispersion of EUDRAGIT® RL:

30.0 g of EUDRAGIT® RL (powder) was dispersed in

132.0 g of demineralized water while stirring on the magnetic stirrer at room temperature, subsequently 9.0 g of Polysorbate 80, 33.5% solution, and

1.5 g of ATEC.

After 2.5 hours of stirring at 45 ° C a low viscosity dispersion is obtained. The dispersion-suspension forms a clear glossy film, which indicates functionality, when dried at room temperature.

Comparative example 17: EUDRAGIT® RS dispersion:

43.0 g of EUDRAGIT® RS (powder) were dispersed in

165.0 g of demineralized water while stirring on the magnetic stirrer at room temperature, subsequently added

13.5 g of Polysorbate 80 and 9.0 g of ATBC.

After 6 hours of stirring at 48 ° C a low viscosity dispersion is obtained. The suspension dispersion forms a clear, very flexible and bright film, which indicates functionality, when dried at room temperature.

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20.0 g of a homogeneous mixture of 70.4% EUDRAGIT® RL PO, 10.6% stearic acid, 4.9% SDS, 7.0% talc and 7.0% Candurin pigment were added , during stirring at room temperature, 113.3 g of demineralized water and stirred for 20 min. Then the temperature increased to 48 ° C. After 2.5 hours the mixture was homogenized with Ultra Turrax for 5 min, a homogeneous dispersion-suspension formed, a nanopolymer dispersion is obtained. The dispersion is subjected to a sieving step using a 0.2 mm sieve, in which 0.2 weight percent of the non-dispersed concentrate is retained in the sieve. The dispersion forms a flexible film when dried at room temperature.

Comparative example 19: EUDRAGIT® RS dispersion (powder):

10.0 g SDS was dissolved in

256.7 g of demineralized water during stirring and

100.0 g of EUDRAGIT® RS was added during stirring and further stirred at room temperature for an additional 24 hours. As a stirrer a propeller stirrer is applied. As a result, a non-opaque nanopolymer dispersion is obtained. The suspension does not form a film when dried at room temperature.

Comparative example 20: EUDRAGIT® RL dispersion:

1.5 g SDS was dissolved in

60 g of demineralized water while stirring on the magnetic stirrer, then 15.0 g of EUDRAGIT® RL (powder) were added

and then heated to 65 ° C.

After stirring for 48 hours, the suspension has a low viscosity. And a white mass is formed, very fragile and fissured, which indicates lack of functionality, when dried at room temperature or 40 ° C.

Example 21: EUDRAGIT® RS dispersion (powder):

10.0 g of SDS was dissolved in

520.0 g of demineralized water during stirring and

100.0 g of EUDRAGIT® RS were added during stirring and subsequently 20.0 g of dibutyl sebacate were added and further stirred at room temperature for an additional 1 hour.

As an agitator, an Ultra Turrax, level 1 is applied. As a result an opaque nanopolymer dispersion is obtained. The dispersion is subjected to a sieving step using a 0.2 mm sieve, in which <1 weight percent of the non-dispersed concentrate is retained in the sieve. The dispersion forms a flexible film when dried at room temperature.

Example 22: EUDRAGIT® RS dispersion:

In 85.0 g of demineralized water, 10.34 g of EUDRAGIT® RS (powder) were added,

1.55 g SDS and

3.1 g of dibutyl sebacate and stirred on the magnetic stirrer. After stirring overnight at room temperature, a dispersion having low viscosity is obtained which forms a flexible clear slightly sticky film when dried at room temperature or 40 ° C.

Example 23: EUDRAGIT® RS dispersion (powder):

In 85.0 g of demineralized water

1.83 g of SDS was mixed

2.42 g of dibutyl sebacate for 2 minutes and

10.75 g of EUDRAGIT® RS was added, and stirred on the magnetic stirrer. After stirring for 24 hours at room temperature, a dispersion having low viscosity is obtained which forms a flexible film when dried at room temperature or 40 ° C.

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1.73 g of SDS were mixed in 85.0 g of demineralized water and

1.73 g of dibutyl sebacate for 2 minutes then

11.54 g of EUDRAGIT® RS were added and stirred on the magnetic stirrer. After stirring for 24 hours at room temperature, a dispersion having low viscosity is obtained which forms a clear flexible film when dried at room temperature or 4 ° C.

Example 25: EUDRAGIT® RS dispersion: In

140.0 g of demineralized water 41.38 g of EUDRAGIT® RS, 6.21 g of SDS and 12.41 g of dibutyl sebacate were added and stirred on the magnetic stirrer. After stirring for 24 hours at room temperature, a dispersion having a low viscosity having a content of 30 percent by weight dry weight is obtained which forms a very flexible film from clear to cloudy when dried at room temperature or 40 ° C.

Example 26: EUDRAGIT® RS dispersion (powder):

15.0 g of sodium dodecyl sulfate (SDS) was dissolved in

338.3 g of demineralized water during stirring and

100.0 g of EUDRAGIT® RS were added during stirring and subsequently 30.0 g of diethyl sebacate were added and further stirred at room temperature for additional 2-3 hours.

As a stirrer a rotating disk is applied (German expression: "Dissolverscheibe") that is operated at 600 rpm. As a result, an opaque nanopolymer dispersion is obtained. The dispersion is subjected to a sieving step using a 0.2 mm sieve, in which 2 percent by weight of the non-dispersed concentrate is retained in the sieve. The dispersion forms a soft and flexible film when dried at room temperature.

Example 27: EUDRAGIT® RS dispersion (powder):

10.0 g of sodium dodecyl sulfate (SDS) was dissolved in

520.0 g of demineralized water during stirring and

100.0 g of EUDRAGIT® RS were added during stirring and subsequently 20.0 g of diethyl sebacate were added and further stirred at room temperature for an additional 2 hours.

As an agitator, an Ultra Turrax, level 1 is applied. As a result an opaque nanopolymer dispersion is obtained. The dispersion is subjected to a sieving step using a 0.2 mm sieve, in which 4 percent by weight of the non-dispersed concentrate is retained in the sieve. The dispersion forms a clear flexible film when dried at room temperature.

Example 28: EUDRAGIT® RL dispersion (powder):

20.0 g of a homogeneous mixture of 69.7% RL PO, 13.9% PEG 6000, 2.4% SDS, 7.0% talc and 7.0% Candurin pigment were added during stirring at room temperature, 113.3 g of demineralized water and stirring for 20 min. Then the temperature increased to 48 ° C. After 2.5 hours a homogeneous dispersion-suspension was formed, a nanopolymeric dispersion is obtained. The dispersion is subjected to a sieving step using a 0.2 mm sieve, in which 0.2 weight percent of the non-dispersed concentrate is retained in the sieve. The dispersion forms a glossy film when dried at room temperature.

Example 28A: EUDRAGIT® RL dispersion (powder):

3.3 g of sodium dodecyl sulfate (SDS) was dissolved in

480.0 g of demineralized water during stirring and

100.0 g of EUDRAGIT® RL was added during stirring and subsequently 16.7 g of dibutyl sebacate were added and further stirred at 48 ° C for an additional 2-3 hours.

As a stirrer a rotating disk is applied (German expression: "Dissolverscheibe") that is operated at 600 rpm. As a result, an opaque nanopolymer dispersion is obtained. The dispersion is subjected to a sieving step using a 0.2 mm sieve, in which 1 percent by weight of the non-dispersed concentrate is retained in the sieve. The dispersion forms a clear flexible film when dried at room temperature.

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30.0 g of EUDRAGIT® RS were dispersed in

165.8.0 g of demineralized water while stirring on the magnetic stirrer at room temperature, 2.4 g of cetyl alcohol, 6.0 g of caprylic acid and 3.0 of Polysorbate 80 were subsequently added. After 24 hours of stirring at 45 ° C a low viscosity dispersion is obtained. The suspension dispersion forms a white and flexible film when dried at room temperature.

Example 30: Dispersion of EUDRAGIT® RL:

30.0 g of EUDRAGIT® RL were dispersed in

129.6 g of demineralized water while stirring on the magnetic stirrer at room temperature, subsequently added

2.4 g decanol.

After 1 hour of stirring at 45 ° C a low viscosity dispersion is obtained. The dispersion-suspension forms a clear, homogeneous and bright film, which indicates functionality, when dried at room temperature.

Example 31: Dispersion of EUDRAGIT® RL:

25.0 g of EUDRAGIT® RL were dispersed in

108.0 g of demineralized water while stirring on the magnetic stirrer at room temperature, subsequently added

2.0 g of hexanol.

After 2 hours of stirring at 40 ° C a low viscosity dispersion is obtained. The dispersion-suspension forms a clear, homogeneous and bright film, which indicates functionality when dried at room temperature.

Example 32: Dispersion of EUDRAGIT® RL:

50.0 g of EUDRAGIT® RL were dispersed in

140.0 g of demineralized water while stirring with a propeller shaker, then 10.0 g of 1-octanol was added

while stirring at room temperature.

After 10 min a high viscosity gel was formed. 200.0 g of water were added and further stirred for 2 hours. A dispersion is obtained that has low viscosity and forms a clear, flexible and bright film, indicating functionality, when dried at room temperature.

Example 33: Dispersion of EUDRAGIT® RL:

50.0 g of EUDRAGIT® RL were dispersed in

128.33 g of demineralized water while stirring with a propeller shaker, then 5.0 g of 1-octanol was added while stirring at room temperature.

After 10 min a high viscosity gel was formed. 91.7 g of water were added and stirred further for 5 hours. A dispersion is obtained that has low viscosity and forms a clear, flexible and bright film, which indicates functionality when dried at room temperature.

Example 34: EUDRAGIT® RS dispersion:

20.0 g of EUDRAGIT® RS were dispersed in

56.0 g of demineralized water while stirring on the magnetic stirrer, subsequently 4.0 g of lactic acid was added while stirring at room temperature.

After 3 hours of stirring, 6.0 g of caprylic acid was added and further stirred for 2 hours. Then the temperature increased to 40 ° C and overnight (approx. 12h) a dispersion is obtained that has low viscosity and forms a clear, flexible and bright film, indicating functionality, when dried at room temperature.

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30.0 g of EUDRAGIT® RL were dispersed in

144.0 g of demineralized water while stirring on the magnetic stirrer at room temperature, subsequently added

6.0 g of behenic acid.

After 48 hours of stirring at 45 ° C a suspension is obtained. The suspension does not form a film when dried at room temperature or 40 ° C.

Comparative Example 36: Dispersion of EUDRAGIT® RL:

30.0 g of EUDRAGIT® RL were dispersed in

144.0 g of demineralized water while stirring with a helix shaker at room temperature, 3.0 g of caprylic acid and 3.0 g of stearic acid were subsequently added.

After 3 hours of stirring at 48 ° C a low viscosity dispersion is obtained. The dispersion forms a clear, homogeneous and bright film, indicating functionality, when dried at room temperature.

Example 37: Dispersion of EUDRAGIT® RL:

30.0 g of EUDRAGIT® RL were dispersed in

91.0 g of demineralized water while stirring on the magnetic stirrer, subsequently 9.0 g of caprylic acid was added while stirring at room temperature.

A dispersion having a low viscosity is obtained within 50 minutes. The dispersion obtained forms a clear, flexible and bright film, which indicates functionality, when dried at room temperature.

Example 38: EUDRAGIT® RS dispersion:

20.0 g of EUDRAGIT® RS were dispersed in

53.7 g of demineralized water while stirring on the magnetic stirrer, then 3.0 g of Lutrol F 127 was added while stirring at room temperature.

After 3 hours of stirring a 6.0 g of caprylic acid was added and further stirred for 2 hours. Then the temperature increased to 40 ° C and overnight (approx. 12h) a dispersion of 35.4% is obtained with very few RS particles and forms a clear, flexible and bright film, indicating functionality, when dried at room temperature.

Example 39: EUDRAGIT® RL dispersion:

30.0 g of EUDRAGIT® RL were dispersed in

156.0 g of demineralized water while stirring on the magnetic stirrer, subsequently 9.0 g of caprylic acid was added while stirring at room temperature.

A dispersion having low viscosity is obtained within 30 minutes. The dispersion obtained forms a clear, flexible and bright film, which indicates functionality, when dried at room temperature.

Example 40: Dispersion of EUDRAGIT® RL:

20.0 g of EUDRAGIT® RL were dispersed in

80.0 g of demineralized water while stirring with a propeller shaker at room temperature, subsequently added

2.0 g of hydroxypropyl methylcellulose (Methocel E5).

After 10 min of stirring at room temperature 3.0 g of caprylic acid was added and further stirred at room temperature for 3 hours. A low viscosity dispersion formed, which forms a clear, flexible and bright film, when dried at room temperature.

5

10

fifteen

twenty

25

30

35

40

20.0 g of EUDRAGIT® RL were dispersed in

96.0 g of demineralized water while stirring on the magnetic stirrer, 4.0 g of caprylic acid were subsequently added

while stirring at room temperature.

A dispersion having low viscosity is obtained within 30 minutes. The dispersion obtained forms a clear, flexible and bright film, which indicates functionality, when dried at room temperature.

Comparative Example 42: EUDRAGIT® RL dispersion:

30.0 g of EUDRAGIT® RL were dispersed in

126.0 g of demineralized water while stirring with a propeller shaker at room temperature, 9.0 g of citric acid were subsequently added.

After 1.5 hours of stirring at 48 ° C a low viscosity dispersion is obtained. The dispersion-suspension forms a clear, homogeneous and bright film, which indicates functionality, when dried at room temperature.

Comparative Example 43: EUDRAGIT® RS dispersion:

30.0 g of EUDRAGIT® RS were dispersed in

91.0 g of demineralized water while stirring with a propeller shaker at room temperature, subsequently added

9.0 g of citric acid.

After 4 hours of stirring at 60 + 80 ° C a white gel of high viscosity is obtained. The dispersion-suspension forms a clear, homogeneous and bright film, which indicates functionality, when dried at room temperature.

Example 44: Dispersion of EUDRAGIT® RL:

50.0 g of EUDRAGIT® RL were dispersed in

240.0 g of demineralized water while stirring with a propeller shaker at room temperature, subsequently added

10.0 g of citric acid.

After 3 hours of stirring at 40 ° C a low viscosity dispersion is obtained. The dispersion forms a clear, homogeneous and bright film, indicating functionality, when dried at room temperature.

Example 45: Dispersion of EUDRAGIT® RL:

50.0 g of EUDRAGIT® RL were dispersed in

340.0 g of demineralized water while stirring with a propeller stirrer at room temperature, subsequently added

10.0 g of lauric acid.

After 5 hours of stirring at 45 ° C a low viscosity dispersion is obtained. The dispersion forms a clear, homogeneous and bright film, indicating functionality, when dried at room temperature.

Example 46: EUDRAGIT® RL dispersion:

30.0 g of EUDRAGIT® RL were dispersed in

132.0 g of demineralized water while stirring on the magnetic stirrer, subsequently 0.4 g of linoleic acid was added

while stirring at 45 ° C.

A dispersion having average viscosity is obtained within 3 hours. The dispersion obtained forms a clear and bright film, which indicates functionality, when dried at room temperature.

5

10

fifteen

twenty

25

30

35

40

50.0 g of EUDRAGIT® RL were dispersed in

237.2 g of demineralized water while stirring with a propeller stirrer at room temperature, subsequently 1.0 g of sodium caprylate and 8.4 g of caprylic acid were added.

After 2 hours of stirring at 48 ° C a low viscosity dispersion is obtained. The dispersion forms a clear, homogeneous and bright film, indicating functionality, when dried at room temperature.

Comparative example 48: EUDRAGIT® RL dispersion:

2.0 g of sodium caprylate were mixed

17.0 g of caprylic acid for 5 min in

480.0 g of demineralized water while stirring with a propeller shaker at room temperature, 100.0 g of EUDRAGIT® RL were subsequently added.

After 2 hours of stirring at 45 ° C a dispersion is obtained which forms a clear flexible film when dried at room temperature or 40 ° C.

To this dispersion was added a mixture of

6.0 g of HPMC,

17.1 g of glycerol triestearate

92.4 g of demineralized water and stirred for 1 hour. The glycerol HPMC-triestearate suspension was poured during stirring to the RL dispersion and further stirred for 1 hour.

The dispersion-suspension was then lyophilized.

40.0 g of lyophilized product were redispersed in 160 g of desm water. by gentle agitation with propeller stirrer at room temperature. The "ready to use" spray suspension was applied on diprophilin pellets without any problem. An immediate release coating with 20% applied on dry substance was obtained.

Example 49: Dispersion of EUDRAGIT® RL:

2.0 g of sodium caprylate were mixed

17.0 g of caprylic acid for 5 min in

480.0 g of demineralized water while stirring with a propeller shaker at room temperature, 100.0 g of EUDRAGIT® RL were subsequently added.

After 2 hours of stirring at 45 ° C a dispersion is obtained which forms a clear flexible film when dried at room temperature or 40 ° C.

To this dispersion was added a mixture of

11.8 g of HPMC,

11.8 g of AEROSIL® 200

94.4 g of demineralized water and stirred for 1 hour. The suspension of HPMC-AEROSIL®200- was poured during stirring to the RL dispersion and further stirred for 1 hour. The dispersion-suspension was then lyophilized.

40.0 g of lyophilized product were redispersed in 160 g of desm water. by gentle agitation with propeller stirrer at room temperature. The "ready to use" spray suspension was applied on diprophilin pellets without any problem. An immediate release coating with 20% applied on dry substance was obtained.

Example 50: Dispersion of EUDRAGIT® RL:

30.0 g of EUDRAGIT® RL were dispersed in

144.0 g of demineralized water while stirring on the magnetic stirrer at room temperature, subsequently added

5

10

fifteen

twenty

25

30

6.0 g ricinoleic acid.

After 2 hours of stirring at 40 ° C a low viscosity dispersion is obtained. The suspension dispersion forms a clear, homogeneous and bright film, which indicates functionality, when dried at room temperature.

Comparative example 51: EUDRAGIT® RL dispersion:

30.0 g of EUDRAGIT® RL were dispersed in

186.0 g of demineralized water while stirring on the magnetic stirrer at room temperature,

subsequently they were added

16.5 g of stearic acid.

After 48 hours of stirring at 45 ° C a suspension is obtained. The suspension does not form a film when dried at room temperature or 40 ° C.

Comparative example 52: EUDRAGIT® RS dispersion:

30.0 g of EUDRAGIT® RS were dispersed in

213.6 g of demineralized water while stirring on the magnetic stirrer at room temperature,

subsequently 14.4 g of tartaric acid and 9.0 g of TEC were added.

After 24 hours of stirring at 45 ° C a low viscosity dispersion is obtained. The dispersion-suspension forms a white film, when dried at room temperature.

Comparative example 53: EUDRAGIT® RL dispersion:

20.0 g of EUDRAGIT® RL were dispersed in

80.0 g of demineralized water while stirring with a propeller shaker at room temperature, subsequently added

2.0 g of hydroxypropyl methylcellulose (Methocel E5).

After 30 min of stirring at room temperature nothing changed, so that the temperature increased to 45 ° C and additionally to 65 ° C and then to 90 ° C. Between 1 h at this temperature the viscosity increased and decreased

slowly during stirring for an additional 4 hours. The dispersion forms a clear, very fragile film, when

Dry at room temperature.

Example 54: EUDRAGIT® RS-RL Spray Coating and Release Tests 117.0 g of Example 24 were stirred and

9.73 of Example 28A were added. Additionally, 10.0 g of magnesium stearate was dispersed by Ultra Turrax for 10 min in 42.3 g of desm water. The Mg stearate suspension was poured into the RS-RL dispersion.

150 g of theophylline pellets (1.0 to 1.25 mm in size) were coated in a Hüttlin Mycrolab device using the suspension dispersions prepared in this example.

Table 1 summarizes the coating conditions for theophylline pellets.

Tablal: Coating conditions for theophylline pellets.

 Formulation

 Example 54

 inlet temperature (° C)

 Four. Five

 bed temperature (° C)

 30-33 ° C

 outlet temperature (° C)

 26-29

 air flow (m3 / h)

 16-18 m3 / h

 Nozzle Diameter (mm)

 0.8

 atomization pressure (bar)

 0.8

 spray rate (ml / min)

 1.3-2.2

The spraying time for the 10 percent weight gain based on the polymer weight was 68 minutes (179.0 g of the dispersions obtained according to Example 54). The coated pellets obtained by the spraying process for the release of theophylline were tested.

The dissolution test was carried out for coated pellets comprising as active substance theophylline 5 using the BP Method II shovel apparatus (Model PTWS, Pharmatest, Hainburg, Germany). The volume of the dissolution media was 900 ml maintained at 37 + 0.5 ° C and a blade speed of 100 rpm was used. The amount of theophylline released from the coated tablets or pellets was determined by UV spectrophotometer at 271 nm for theophylline. The pellets were placed for 120 min in 0.1 N HCl.

Example of 10% w / p sustained release coated theophylline pellets based on polymer formulation 10 compared to the standard: The example (comparative) in the left column is based on commercially available EUDRAGlT® RS dispersion of EUDRAGIT® RL, respectively (EuDRAGIT® RS 30D / EUDRAGIT® RL 30D). The example in the right column is an inventive example where the aqueous dispersion is made of EUDRAGIT® RS and EUDRAGIT® RL powder.

 Composition

   90% EUDRAGIT® RS (dry weight) 10% EUDRAGIT® RL (dry weight) + 20% triethyl citrate (TEC) + 50% talc 90% EUDRAGIT® RS PO 10% EUDRAGIT® RL PO + 13.9% SDS + 15.2% DBS + 50% talc

 Means, medium

 [min] Drug release [%] 0.1 N HCl Drug release [%] 0.1 N HCl

 0.1 N HCl

 0 -0.02 0.05

 0.1 N HCl

 30 0.31 0.33

 0.1 N HCl

 60 0.80 1.52

 0.1 N HCl

 90 1.44 3.03

 0.1 N HCl

 120 2.20 4.80

Example 55: Theophylline pellets were coated in a fluidized bed coater using the dispersion of Comparative Examples 14 and 48 applying similar coating conditions as in Example 54. After drying the pellets they were homogeneously coated with a glossy film. Drug release [%] similar to Example 54 in demineralized water and 0.1 N HCl was tested.

(RLPO = EUDRAGIT® RL (powder))

 Comparative example 14 Comparative example 48 Comparative example 14 Comparative example 48

 Composition

 66, RLPO% 6.7% TEC 6.7% PS80 12.0% Mg stearate 8.0% HPMC 70.0% RLPO I, 4% Na II caprylate, 8% caprylic acid 12, 5% glycerol triestearate 4.2% HPMC 66, /% RLPO 6.7% TEC 6.7% PS80 12.0% Mg stearate 8.0% HPMC 70.0% RLPO I, 4% Na II caprylate, 8% 12.5 caprylic acid glycerol triestearate HPMC

 [min]

 Drug release [%] water desm. Drug release [%] water desm. Drug release [%] 0.1 N HCl Drug release [%] 0.1 N HCl

 0

 -0.12 0.00 0.01 -0.01

 Comparative example 14 Comparative example 48 Comparative example 14 Comparative example 48

 Composition

 66, RLPO% 6.7% TEC 6.7% PS80 12.0% Mg stearate 8.0% HPMC 70.0% RLPO I, 4% Na II caprylate, 8% caprylic acid 12, 5% glycerol triestearate 4.2% HPMC 66, /% RLPO 6.7% TEC 6.7% PS80 12.0% Mg stearate 8.0% HPMC 70.0% RLPO I, 4% Na II caprylate, 8% 12.5 caprylic acid glycerol triestearate HPMC

 5

 44.95 48.10 56.20 40.50

 fifteen

 99.32 97.81 99.08 97.51

 30

 99.90 99.23 100.04 99.25

 Four. Five

 99.79 99.44 99.79 99.48

 60

 99.91 99.66 99.72 99.16

 90

 100.00 100.00 100.00 100.00

Claims (6)

5 10 fifteen twenty 25 30 35 40 Four. Five 1. A process of converting a copolymer of solid (meth) acrylate into a dispersed form by preparing an aqueous dispersion comprising the components (a) a copolymer of (meth) acrylate which is composed of free radical polymerized methyl methacrylate, ethyl acrylate and a 2-trimethylammonioethyl methacrylate salt, present in solid form as a powder or as a granule, where The (meth) acrylate copolymer is composed of 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and 7 to 2% by weight of a salt of 2-trimethylammonioethyl methacrylate, in the that the percentages by weight add up to 100% or The (meth) acrylate copolymer is composed of 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and more than 7 to 12% by weight of a salt of 2-trimethylammonioethyl methacrylate , in which the percentages by weight add up to 100%, (b) up to 50% by weight calculated based on the (meth) acrylate copolymer (a) of a dispersing agent selected from the groups of (b) i) plasticizers in combination with emulsifiers and / or (b) ii) selected from one or more of the groups consisting of (b) ii-i) fatty alcohols having 6 to 18 carbon atoms, (b) ii-ii) water soluble salts of saturated or unsaturated carboxylic acids having 6 to 18 carbon atoms, (b) ii-iii) unsubstituted monocarboxylic acids having 6 to 18 carbon atoms, (b) ii-iv) hydroxycarboxylic acids having 6 to 18 carbon atoms. (c) water mixing components (a), (b) and (c) to give a suspension that becomes an aqueous dispersion during the conversion of the solid (meth) acrylate copolymer into the dispersed form, wherein the plasticizer with respect to component (b) is selected from the group consisting of alkyl citrates, alkyl phthalates, alkyl sebacate, polyethylene glycols or mixtures thereof and The emulsifier with respect to component (b) is selected from the group consisting of fatty alkyl sulfates, sucrose stearate, polysorbates or mixtures thereof or of sodium salts of fatty alcohol sulfates, sulphosuccinates, partial fatty acid esters of polyhydric alcohols, partial esters of sorbitan fatty acids, partial esters of polyhydroxyethylene sorbitan (mono-ester) fatty acids, ethers of fatty alcohols and polyhydroxyethylene, esters of fatty acids and polyhydroxyethylene or block copolymers of ethylene oxide and propylene oxide, characterized by that The (meth) acrylate copolymer is converted into the dispersed form by means of the presence of the dispersing agent at a temperature below 45 ° C. 2. The process according to claim 1, characterized in that the components (b) ii) - i) a (b) ii) - iv) are used in combination with a plasticizer. 3. The process according to claims 1 or 2, characterized in that the fatty alcohol with respect to component (b) ii-i) is selected from the group consisting of hexanol, octanol, decanol, dodecanol, tetradecanol and hexadecanol and mixtures thereof. same. 4. The process according to any one of claims 1 to 3, characterized in that the water-soluble salt with respect to component (b) ii-ii) is a salt of a carboxylic acid selected from the group consisting of caprylic acid, acid caprinic, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, elewestlaric acid and arachidonic acid, or mixtures thereof. 5. The process according to any one of claims 1 to 4, characterized in that the unsubstituted monocarboxylic acid with respect to component (b) ii-iii) is selected from the group consisting of caproic acid, caprylic acid, caprinic acid, acid lauric, linoleic acid, myristic acid or mixtures thereof. 6. The process according to any one of claims 1 to 5, characterized in that the hydroxycarboxylic acid with respect to component (b) ii-iv) is dihydroxyethylglycine, 3-hydroxy-4-trimethylammonium-butanoate, citric acid, cyclobutyrol, acid 3-dehydroquinic, 2,3-dihydroxy-3-methylpentanoic acid, 2,3-dihydroxybenzoic acid, 2,3-dihydroxymenedic acid, 5-hydroxysalicylic acid (gentisic acid), homocitric acid, isocitric acid, isosacarinic acid, 5 mandelic acid , mevalonic acid, monatin, pamoic acid, prepenic acid, ricinoleic acid, salicylic acid, shikimic acid or mixtures thereof.